Lupus erythematosus and lupus nephritis - Symptoms

The symptoms of lupus nephritis are polymorphic and consist of a combination of various signs, some of which are specific to systemic lupus erythematosus.

• Increased body temperature (from subfebrile to high fever).
• Skin lesions: the most common are erythema of the face in the form of a “butterfly”, discoid rashes, however, erythematous rashes in other locations are possible, as well as rarer types of skin lesions (urticarial, hemorrhagic, papulonecrotic rashes, reticular or dendritic livedo with ulceration).

• Joint damage is most often represented by polyarthralgia and arthritis of the small joints of the hands, rarely accompanied by joint deformation.
• Polyserositis (pleurisy, pericarditis).
• Peripheral vasculitis: capillary disease of the fingertips, less often of the palms and soles, cheilitis (vasculitis around the red border of the lips), enanthem of the oral mucosa.
• Lung damage: fibrosing alveolitis, discoid atelectasis, high position of the diaphragm, leading to the development of restrictive respiratory failure.
• CNS lesions: lupus cerebrovasculitis, most often manifested by intense headaches, seizures, mental disorders. Rare lesions of the nervous system include transverse myelitis, which has an unfavorable prognostic value.
• Heart damage: myocarditis develops more often, Libman-Sachs endocarditis less often; coronary vessel damage is also possible.
• Kidney damage: glomerulonephritis of varying severity.
• Trophic disorders: rapid weight loss, alopecia, nail damage.
• Lymphadenopathy.

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Pathomorphology of lupus erythematosus and lupus nephritis

The morphological picture of lupus nephritis is characterized by significant polymorphism. Along with histological changes characteristic of glomerulonephritis in general (proliferation of glomerular cells, expansion of the mesangium, changes in the basement membranes of the capillaries, damage to the tubules and interstitium), specific (although not pathognomonic) morphological signs of lupus nephritis are noted: fibrinoid necrosis of capillary loops, pathological changes in cell nuclei (karyorrhexis and karyopyknosis), sharp focal thickening of the basement membranes of the glomerular capillaries in the form of "wire loops", hyaline thrombi, hematoxylin bodies.

Immunohistochemical examination reveals IgG deposits in the glomeruli, often in combination with IgM and IgA, as well as the C3 component of complement and fibrin. Electron microscopic examination reveals deposits of immune complexes of various localizations: subendothelial, subepithelial, intramembranous and mesangial. The pathognomonic sign of lupus nephritis is intraendothelial virus-like inclusions in the glomerular capillaries, resembling paramyxoviruses.

In 50% of cases, in addition to glomerular changes, tubulointerstitial changes are also observed (in the form of dystrophy and atrophy of the tubular epithelium, infiltration of the interstitium by mononuclear cells, foci of sclerosis). As a rule, the severity of tubulointerstitial changes corresponds to the severity of the glomerular lesion; isolated tubulointerstitial lesion occurs extremely rarely. In 20-25% of patients, damage to small renal vessels is detected.

Clinical variants of lupus nephritis

The modern clinical classification of lupus nephritis was proposed by I.E. Tareeva (1976). Depending on the severity of lupus nephritis symptoms, the nature of the course, and the prognosis, several variants of lupus nephritis can be distinguished, which require different therapeutic approaches.

• Active nephritis.
  • Rapidly progressive lupus nephritis.
  • Slowly progressive lupus nephritis:
    • with nephrotic syndrome;
    • with pronounced urinary syndrome.
• Inactive nephritis with minimal urinary syndrome or subclinical proteinuria.
• Symptoms of lupus nephritis depend on its morphological variant.
• Rapidly progressive lupus nephritis develops in 10-15% of patients.
  • According to the clinical picture, it corresponds to classical subacute malignant glomerulonephritis and is characterized by a rapid increase in renal failure caused by the activity of the renal process, as well as nephrotic syndrome, erythrocyturia and arterial hypertension, mainly severe.
  • A characteristic feature of rapidly progressive lupus nephritis is the frequent (in more than 30% of patients) development of DIC syndrome, clinically manifested by bleeding (skin hemorrhagic syndrome, nasal, uterine, gastrointestinal bleeding) and thrombosis and characterized by such laboratory signs as the appearance or increase of thrombocytopenia, anemia, decreased fibrinogen content in the blood, and an increase in the concentration of fibrin degradation products in the blood.
  • Often, rapidly progressing lupus nephritis is combined with damage to the heart and central nervous system.
  • Morphologically, this variant most often corresponds to diffuse proliferative lupus nephritis (class IV), often with crescents.
  • The isolation of this form of the disease is due to the severe prognosis, the similarity of the clinical picture with other rapidly progressing nephritis, and the need to use the most active therapy.
• Active lupus nephritis with nephrotic syndrome develops in 30-40% of patients.

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Lupus nephritis

Lupus nephritis is one of the most common causes of nephrotic syndrome in young women. The peculiarities of lupus nephrotic syndrome include the rarity of very high proteinuria (such as is observed, for example, in renal amyloidosis) and, consequently, lesser severity of hypoproteinemia and hypoalbuminemia, frequent combination with arterial hypertension and hematuria, lesser tendency to relapse than in chronic glomerulonephritis. Most patients have hypergammaglobulinemia, sometimes pronounced, and, unlike patients with other etiologies of nephrotic syndrome, moderately elevated levels of a ₂ -globulins and cholesterol. Morphological examination usually reveals diffuse or focal proliferative lupus nephritis, less often membranous (III, IV and V classes, respectively).

• Active lupus nephritis with pronounced urinary syndrome, characterized by proteinuria from 0.5 to 3 g/day, erythrocyturia,
  leukocyturia, is observed in approximately 30% of patients.
  • Hematuria is an important criterion for the activity of lupus nephritis. Most patients have severe and persistent microhematuria, usually combined with proteinuria, and in 2-5% of cases, macrohematuria is noted. Isolated hematuria (hematuric nephritis) is rarely observed.
  • Leukocyturia may be a consequence of both the lupus process itself in the kidneys and the addition of a secondary urinary tract infection. To differentiate these processes (to decide on the timely initiation of antibacterial therapy), it is advisable to examine the leukocyte formula of the urine sediment: in the case of an exacerbation of lupus nephritis, lymphocyturia is detected (lymphocytes more than 20%), and in the case of a secondary infection, neutrophils predominate in the urine sediment (more than 80%).
  • Arterial hypertension is observed in more than 50% of patients with this form of lupus nephritis.
  • The morphological picture is equally often represented by proliferative lupus nephritis and mesangial forms of the disease (classes II, III, IV).
  • If in patients with rapidly progressing lupus nephritis and active lupus nephritis with nephrotic syndrome, the clinical picture is dominated by signs of kidney damage, then in patients with severe urinary syndrome, extrarenal lesions (skin, joints, serous membranes, lungs) come to the fore.
• Lupus nephritis with minimal urinary syndrome is characterized by proteinuria less than 0.5 g/day (subclinical proteinuria) without leukocyturia and, most importantly, without erythrocyturia. The disease proceeds with normal renal function and without arterial hypertension. Identification of this type of nephritis is important for the choice of therapy; the intensity of treatment is determined by the lesions of other organs. Morphological changes correspond to class I or II, although they are sometimes accompanied by tubulointerstitial and fibroplastic components.

Such clinical symptoms of lupus nephritis as renal failure and arterial hypertension have serious prognostic significance.

• Renal failure is the main symptom of rapidly progressive lupus nephritis. The rate of increase in creatinine concentration in the blood is important for diagnosis: doubling of creatinine content in less than 3 months serves as a criterion for rapid progression. A small proportion of patients with lupus nephritis (5-10%) have acute renal failure, which, in addition to high activity of nephritis, can be caused by DIC syndrome, thrombotic microangiopathy of intrarenal vessels in antiphospholipid syndrome (see "Kidney damage in antiphospholipid syndrome"), secondary infection, and drug-induced kidney damage as a result of antibacterial therapy. Unlike Bright's nephritis, in patients with systemic lupus erythematosus, the development of renal failure does not mean the absence of disease activity even in the presence of clinical signs of uremia, and therefore some patients need to continue immunosuppressive therapy even after the start of hemodialysis.
• Arterial hypertension occurs in an average of 60-70% of patients with lupus nephritis. The incidence of arterial hypertension and hemodynamics are closely related to the degree of nephritis activity (thus, arterial hypertension is observed in 93% of patients with rapidly progressing nephritis, and in 39% with inactive nephritis). The damaging effect of arterial hypertension on the kidneys, heart, brain, and blood vessels in systemic lupus erythematosus is aggravated by autoimmune damage to these same target organs. Arterial hypertension worsens overall and renal survival, increases the risk of death from cardiovascular complications and the development of chronic renal failure. Normalization of arterial pressure upon achieving remission of lupus nephritis also confirms the relationship between arterial hypertension in lupus nephritis and the severity of the process activity. Nephrosclerosis affects arterial pressure only in cases where it reaches significant severity. In moderate activity of lupus nephritis and systemic lupus erythematosus in general, antiphospholipid syndrome plays a special role as a cause of arterial hypertension. The risk of developing "steroid" arterial hypertension in patients with systemic lupus erythematosus is 8-10%, and in case of kidney damage - up to 20%. For the development of "steroid" arterial hypertension, not only the dose but also the duration of treatment with glucocorticoids are important.

Classification of lupus erythematosus and lupus nephritis

Depending on the nature of the onset, the rate of progression of lupus erythematosus and lupus nephritis, and the polysyndromic nature of the process, acute, subacute, and chronic course of systemic lupus erythematosus are distinguished (classification by V.A. Nasonova, 1972).

• In acute cases, the disease begins suddenly with high fever, polyarthritis, serositis, skin rashes. Already at the onset of the disease or in the coming months, signs of damage to vital organs are noted, mainly the kidneys and the central nervous system.
• In the most common, subacute course, the disease develops more slowly, in waves. Visceritis does not appear simultaneously with the damage to the skin, joints, serous membranes. The polysyndromic nature characteristic of systemic lupus erythematosus develops over 2-3 years.
• The chronic course of the disease is manifested over a long period of time by relapses of various syndromes: articular, Raynaud's, Werlhof's; visceral lesions develop late.

Lupus nephritis is the most serious organ lesion in systemic lupus erythematosus, found in 60% of adult patients and 80% of children, however, lupus nephritis is an early symptom of lupus, along with arthralgia, skin and serous membrane lesions, only in 25% of patients, and among patients with the onset of the disease over 50 years of age - less than 5%. The incidence of lupus nephritis depends on the nature of the course and activity of the disease: most often the kidneys are affected in acute and subacute cases and much less often in chronic cases. Lupus nephritis, as a rule, develops in the first years after the onset of systemic lupus erythematosus, with high immunological activity, during one of the exacerbations of the disease. In rare cases, this kidney lesion is the first symptom of lupus nephritis, preceding its extrarenal manifestations (the "nephritic" mask of systemic lupus erythematosus, usually accompanied by nephrotic syndrome, which may recur in some patients for several years before the development of systemic manifestations or signs of immunological activity of the disease). The most acute and active forms of nephritis develop mainly in young patients; in older people, a more calm course of both lupus nephritis and systemic lupus erythematosus is more often detected. As the duration of the disease increases, the incidence of lupus nephritis increases.

Symptoms of lupus nephritis are extremely diverse: from persistent minimal proteinuria, which does not affect the well-being of patients and has virtually no effect on the prognosis of the disease, to severe subacute (rapidly progressing) nephritis with edema, anasarca, arterial hypertension and renal failure. In 75% of patients, kidney damage develops against the background of a full-blown clinical picture of the disease or in the presence of 1 or 2 symptoms (usually arthralgia, erythema or polyserositis). In such cases, sometimes it is the addition of signs of kidney damage that allows the correct diagnosis to be made, despite the absence of any symptoms characteristic only of lupus nephropathy.

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Morphological classification of lupus erythematosus and lupus nephritis

According to the morphological classification of domestic authors, the following forms of lupus nephritis are distinguished.

• Focal lupus proliferative nephritis.
• Diffuse proliferative lupus nephritis.
• Membranous.
• Mesangioproliferative.
• Mesangiocapillary.
• Fibroplastic.

The morphological classification of lupus nephritis, proposed by WHO in 1982 and approved in 2004 by the International Society of Nephrology, which made additions and clarifications to it, includes 6 classes of changes.

• Class I - minimal mesangial lupus nephritis: with light microscopy, the glomeruli appear normal, and with immunofluorescence microscopy, immune deposits are detected in the mesangium.
• Class II - mesangioproliferative lupus nephritis: light microscopy reveals varying degrees of mesangial hypercellularity or expansion of the mesangial matrix.
• Class III - focal lupus nephritis: light microscopy reveals active or inactive segmental (less than 50% of the vascular bundle is affected) or global (more than 50% of the vascular bundle is affected) endocapillary or extracapillary glomerulonephritis, also involving the mesangium, in less than 50% of the glomeruli.
• Class IV - diffuse lupus nephritis: light microscopy reveals segmental or global endocapillary or extracapillary glomerulonephritis in more than 50% of glomeruli, including necrotizing changes, as well as mesangial involvement. Subendothelial deposits are usually found in this form.
• Class V - membranous lupus nephritis is characterized by the presence of subepithelial immune deposits detected by immunofluorescence or electron microscopy and significant thickening of the glomerular capillary wall.
• Class VI - sclerosing lupus nephritis, in which more than 90% of the glomeruli are completely sclerosed.

When comparing the last two classifications, their similarity can be revealed: class II according to the WHO classification is close to mesangioproliferative glomerulonephritis according to the classification of V.V. Serov, class V according to the WHO classification completely corresponds to membranous nephritis in the domestic classification, class VI - fibroplastic, however, classes III and IV according to the WHO classification are broader concepts than focal and diffuse lupus nephritis according to the classification of V.V. Serov, since they include, in addition to focal and diffuse proliferative lupus nephritis, a number of cases of mesangioproliferative and mesangiocapillary glomerulonephritis according to the domestic classification. The morphological type of the disease is the basis for choosing the optimal therapy for lupus nephritis.